Our broad research aim is to identify and validate biomarkers that may improve the effectiveness of screening and clinical treatment efforts for lead poisoning. Lead is an important environmental toxin. Hundreds of thousands of children have blood lead levels that may be neurotoxic. A common genetic polymorphism in delta-aminolevulinate dehydratase (ALAD), the second enzyme in the heme biosynthesis pathway, has been associated with elevated blood-lead levels in children and adults. This may be due to a greater affinity of the variant ALAD-2 enzyme for lead binding. It has been suggested that this trait may represent a biomarker of susceptibility to lead toxicity. We propose to confirm and extend this observation, controlling for potential confounding variables. We hypothesize that ALAD genotype will provide a useful biomarker of the effectiveness of chelation therapy used in the treatment of lead poisoning. We also hypothesize that the ALAD-2 enzyme will be protective of lead toxicity by sequestering lead from sensitive sites of neurotoxic action. These issues will be investigated in a cohort of 8,000 children who present for lead screening at the Boston Children's Hospital. We will also study 2,300 children who are being treated for lead intoxication at the Boston Children's Hospital Lead Clinic. Finally, we will study two populations of environmentally lead-exposed children to determine if ALAD genotype is associated with susceptibility to neuropsychological dysfunction.